We propose to study the relation between exposure to metals-in both early life and adult life-and the risk of developing Alzheimer's disease (AD), and whether those exposures are associated with changes in levels of amyloid-? species (A?) in blood and brain. We will conduct a case-control study with an estimated 183 cases and 270 controls recruited from the Edith Nourse Rogers Memorial Bedford VA Medical Center (Bedford VA). Furthermore, we propose to additionally examine whether early and later life metal exposures are associated with worse cognitive function among the controls. The Bedford VA provides a uniquely suited setting in which to conduct this research as the facility serves AD patients and has a dental clinic on-site from which we can recruit appropriate controls with availability of tooth samples. The source population for both cases and controls are veterans in the Bedford, MA area. In addition, essentially all clinical AD cases go to autopsy, thus case status can be confirmed neuropathologically and brain tissue can be collected for analyses. Early life exposure to metals will be assessed by measuring metals in adult tooth enamel (using laser-ablation inductively coupled plasma mass spectrometry). Controls will be recruited from the Bedford VA dental clinic when they are having a tooth extracted for other reasons, and teeth will be collected from cases if they are having a tooth extracted for other reasons while alive, or at autopsy. Adult exposure to lead (Pb) will also be measured with the non-invasive K-shell X-ray Fluorescence (KXRF) technique with which we have extensive past experience. A? species will be measured in blood samples collected at study visits and temporal cortex brain tissue collected at autopsy. Cognitive function will be tested among the controls at their study visit. This study will be the first to examine the association between adult exposure to metals and AD using biomarkers of exposure, and the first of any kind to explore the association between early life metal exposures and AD in humans-a hypothesis suggested for Pb exposure from animal research, but essentially untestable in humans without the biomarker of such early exposure that teeth can provide.